It is postulated that tumors arise as a result of a multistepped process. The objective of this project is to isolate the putative surveillance-susceptible intermediate cell types, then determine both the class of the immune or nonimmune response (e.g., Ig, CMI, NK, NC) that effects their rejection and how these intermediate cell types might escape immune or nonimmune elimination to grow progressively. In this regard, we have shown that normal cells (N-cells) can be transformed by chemical carcinogens to an intermediate cell types (I-cells); I-cells are tumorigenic yet susceptible to host-protective mechanism such that they grow in surveillance-deficient individuals but do not grow progressively in normal individuals. From these I-cells, variants can be derived which have escaped the host-protective mechanisms (C-cells) such that these cells grow progressively in normal individuals. Thus, we have reconstructed the postulated autochthonous pathway from normal to cancerous as predicted by the immune surveillance hypothesis: normal to transformed and surveillance-susceptible to transformed and surveillance resistant (i.e., N to I to C). In addition to the analysis of the immune and nonimmune response that mediates the rejection of I-cells and how C-cells escape rejection, the transformed I and C cells are being analyzed to determine the number of different tumor-associated antigens that can be expressed by independent I cells and the gene-level events required for the N to I step as well as the I to C step. (IB)